1609392-27-9

Deucravacitinib, a highly selective allosteric TYK2 inhibitor, received its first approval from the FDA in 2022 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy protein and lipid kinases and pseudokinases with the exception of BMPR2 (IC50 = 193 nM) and JAK1 JH2 pseudokinase domain (IC50 = 1 nM). Despite its potent affinity for JAK1 JH2, deucravacitinib elicited low functional activity in a JAK1/JAK3-dependent IL-2 stimulated cellular assay. BMS-986202 displays >10,000-fold selectivity for TYK2 JH2 over a diverse panel of 273 kinases and pseudokinases that include JAK family members. Like deucravacitinib, its high binding affinity to JAK1 JH2 (IC50 = 7.8 nM) did not translate to functional activity in the cellular assay.

The crystalline free base form of deucravacitinib exhibited poor aqueous solubility (5.2 μg/mL), which was still acceptable for preclinical studies. It showed moderate half-lives of 4?5 h across species (mouse, dog, and monkey). Excellent exposures and high bioavailability (F > 85%) in mice, dogs, and monkeys were obtained from oral pharmacokinetic studies at a 10 mpk dose. Following oral administration of deucravacitinib, the major metabolite in human plasma was the cyclopropyl carboxamide hydrolytic cleavage product 4 (6-amino-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide).